Hyperlipoproteinemia & Fatty Liver: An Overview

Fredrickson's Classification

Six Types

1. Type I (Familial chylomicronemia syndrome)
2. Type IIa (Familial hypercholesterolemia)
3. Type Iib
4. Type III (Apo E defect, remnant disease, broad beta disease, and Familial Dysbetalipoproteinemia)
5. Type IV
6. Type V

These six types have been grouped into three categories:

• Hypercholesterolemia
• Hypertriglyceridemia
• Both

Hypercholesterolemia 

Tendon xanthoma: Small eruptive lesions present along the line of attachment of tendons.

Accelerated atherosclerosis.

Hypertriglyceridemia

• Eruptive xanthomas
• Recurrent pancreatitis
• Lipemia retinalis

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What is the difference between phrynoderma and eruptive xanthoma?

Both hypercholesterolemia and hypertriglyceridemia exhibit a combination of clinical features from both conditions.

Phrynoderma	Eruptive Xanthoma
At the tip of the lesion, the keratin plug is seen - Follicular Hyperkeratosis Causes: Vit A deficiency - Essential fatty acid deficiency	Small eruptive lesions along the elbowswithout a keratin plug.

Hyperlipoproteinemia with Isolated Elevation of Cholesterol, Triglycerides, and Both

Type IIa (only cholesterol elevated)

• Type I, IV, and V (only elevated triglycerides)
• Type IIb and III (mixed)

Type IIa Hyperlipoproteinemia

• Familial hypercholesterolemia: only cholesterol elevated.
• Autosomal Dominant condition with a gene dose effect
• LDL receptor defect
  • One allele affected: LDL receptor defective individual (LDL receptor activity <25% of normal)
    • Gene dose effect: Milder
  • Both alleles affected: LDL receptor-negative individual (LDL receptor activity <8% of normal)
    • Gene dose effect: Severe

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Type I Hyperlipoproteinemia

• Familial chylomicronemia syndrome
  • Apo C II or LPL defect
  • Isolated elevation of TGL (>1500mg/dl)
• Clinical features: eruptive xanthoma, recurrent pancreatitis, and lipemia retinalis.
• LPL (lipoprotein lipase) activity is low.

LPL Activity Estimation

Post-heparinized blood samples are used because heparin in circulation competes with heparan sulfate on vessel walls, causing enzymes to detach from the vessel wall and attach to circulating heparin. If LPL activity is low in post-heparinized individuals: Apo C II defect or an LPL defect. Mixing study: To differentiate Apo C defect from LPL defect.

• To post heparinized plasma from patients, add an equal amount of pooled normal plasma which acts as a source of apo C II.
• Following mixing, if LPL activity normalizes: apo C II defect and it responds to FFP administration.
• Following mixing, if LPL activity does not normalize: LPL defect.

Type IV and Type V Hyperlipoproteinemia's 

Familial hypertriglyceridemia; autosomal dominant conditions.

↑ rate of VLDL synthesis and ↓ rate of VLDL catabolism.

Type IV: only genetic defect; Type V: primary (genetic) defect + secondary hypertriglyceridemia.

Secondary Causes of Hypertriglyceridemia

• Obesity
• DM
• Nephrotic syndrome
• Oral Contraceptive Pills (OCP's)
• Von Gierke's disease

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Type IIb Hyperlipoproteinemia

Familial combined hyperlipidemia has two defects:

a) Increase in VLDL synthesis: ↑ TGL.

b) Small LDL particles, higher the number of LDL particles → rate of LDL clearance ↓→ LDL

accumulation in circulation → ↑ cholesterol levels (as LDL carries cholesterol).

Type III Hyperlipoproteinemia

• AKA Apo E defect/remnant disease/broad beta disease and familial dysbetalipoproteinemia.
• Remnant lipoproteins are not cleared of circulation. ·
• Elevation of both cholesterol and TGL *caused by a homozygous E2 mutation.

Lipoprotein Electrophoresis

Glass slide with support medium (Agarose)

↓

On one end of a glass slide serum lipoprotein applied by micropipette

↓

Glass slide is placed in electrophoretic tank, filled alkaline buffer

(pH - 8.3) - gives a negative charge to lipoprotein.

↓

To the point of application, a negatively charged electrode is connected and to

opposite point to positively charged electrode

↓

Lipoproteins move towards the oppositely charged electrode on

passing electric current

• Migration is affected by
  • No. of negative charges that they carry
  • Size (larger particles will not be able to move) alpha
• band or HDL: moves farthest because it has ↑ phospholipid, ↑ protein content, and more negative charges.
• Chylomicron band: moves closest because of its huge size.
  • In a lipoprotein electrophoresis fasting sample is taken, normally, a chylomicron band will not be present because it is a product of dietary triacylglycerol
  • Presence of chylomicron band seen in:
  • The patient is not fasting (↑ chylomicron).
  • Familial chylomicronemia syndrome (↑ chylomicron).
  • LpX (lipoprotein X): Causes include LCAT deficiency (↑ Discoidal HDL) & obstructive jaundice.
    • LCAT normally converts discoidal HDL to spheroidal HDL.
    • LCAT deficiency presents as fish eye disease and chronic kidney disease.

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Fatty Liver

Fat accumulation in the liver

Causes

• Increased input
  • Dietary fat is never a cause of fatty liver, as it gets absorbed as chylomicrons, which never reach the liver but rather extrahepatic tissues.
  • Excessive peripheral lipolysis: Hormone-sensitive lipase cleaves triacylglycerol present in adipose tissue → glycerol and fatty acids →liver (for oxidation of fatty acids); excessive fatty acids reaching the liver cause fatty liver.
  • Anything stimulating hormone-sensitive lipase can cause fatty liver.
  • Hormone-sensitive lipase is inhibited by insulin.
  • Conditions with low insulin levels (such as diabetes mellitus and starvation) can lead to fatty liver changes by causing excessive peripheral lipolysis.
• Increased synthesis of lipid within the liver: anabolism—obesity and alcoholism.
• Decreased output of lipid from the liver:
  • Defective VLDL formation/organisation: Choline deficiency, Essential Fatty Acid deficiency, CCl poisoning, chronic alcoholism, puromycin, orotic aciduria
  • Formation of lipoprotein:
    • An outer amphipathic layer : phospholipids (phosphatidylcholine) + cholesterol.
    • Inner non-polar lipid core: Triacylglycerol + cholesterol ester (formed by fatty acids)
    • After formation, lipoproteins attach to apoproteins (from RER) and go to Golgi bodies.

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Important Points to Remember

• The hyperlipoproteinemia, which presents with only an elevation of cholesterol: Type Iia.
• Puromycin: protein synthesis inhibition so Apo proteins are not synthesized, which causes fatty liver changes.
• The hyperlipoproteinemias, which present with only an elevation of triglycerides: Type I, Type IV , Type V
• Lipoprotein X is a feature of obstructed jaundice and LCAT deficiency.
• A broad beta band in lipoprotein electrophoresis is a feature of Apo E defect.

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Important MCQs

Q. Hypertriglyceridemia is seen in all, except:

1. Von-Gierkes disease
2. Alcoholism
3. Type IIa Hyperlipoproteinemia
4. Nephrotic syndrome

Q. Tendon xanthomas occur in

1. Type IIa dyslipidemia
2. Type I
3. Type IV
4. Type V

Q. The pathognomic feature of type III hyperlipoproteinemia is

1. Tendon Xanthoma
2. Palmar eruptive xanthoma
3. Lipemia retinalis
4. Pancreatitis

Q. All of the following are causes of fatty liver except:

1. Obesity
2. Prolonged starvation
3. Alcoholism
4. Choline excess

Q. A 15 year old child presents with repeated episodes of pancreatitis. Serum triglyceride concentration is 1100 mg/dL, Cholesterol is 250 mg/dL. Lipoprotein lipase activity is low. The diagnosis is:

1. Type I Hyperlipoproteinemia
2. Type IIa Hyperlipoproteinemia
3. Type III Hyperlipoproteinemia
4. Type IV Hyperlipoproteinemia

Q. A patient presents with corneal haziness, high urea, high creatinine, high potassium. Suspecting LCAT deficiency, Lipoprotein electrophoresis was performed. His HDL was undetectable. Name the abnormal lipid found in the electrophoresis?

1. Spheroidal HDL3
2. LpX
3. HDL2
4. Bread Beta ban

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